Hydroquinones

ABSTRACT

A process is disclosed for producing (S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol from either alkyl(R)-2-benzyloxy-3-hydroxy-2-methyl-propionate or (S)-2,2,4-trimethyl-1,3-dioxolan-4-ethanol including intermediates in this synthesis.

This is a division of application Ser. No. 905,361, filed May 12, 1978.

BACKGROUND OF THE INVENTION

According to prior art processes, natural optically active Vitamin Ewhich is the 2R, 4'R, 8'R isomer of α-tocopherol, is manufactured from aknown aldehyde of the formula: ##STR1## wherein R_(x) is lower alkyl,lower alkanoyl or benzyl.

The prior art process for producing this aldehyde, however, presentsmany problems. For example, an acid firstly obtained in the manufactureof the above aldehyde is always produced in racemic form and can beseparated into its optical antipodes only in an extremely complicatedmanner. Further, the undesired antipode of the acid cannot be racemizedand restored into the process which accordingly leads to considerablematerial loss.

We have invented an improved process for producing the aldehyde offormula I via optically active intermediates which avoids thedifficulties of the prior art.

SUMMARY OF THE INVENTION

According to the present invention, a compound of the formula: ##STR2##is oxidized with a cerium(IV) salt or complex to form quinones of theformulas: ##STR3## wherein R is lower alkyl; R₁ and R₂ each are loweralkyl or R₁ is phenyl and R₂ is hydrogen; and R₃ is hydrogen or hydroxy.

Compounds II and/or III can be treated with an acid to obtain a compoundof the formula: ##STR4## wherein R₃ is as above.

Compound IV in turn can be converted by reductive aromatization into achromane derivative of the formula: ##STR5## with cleavage of hydroxywhere R₃ is other than hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "lower alkyl" refers to straight or branchedchain alkyl groups having from 1 to 4 carbon atoms (e.g. methyl, ethyl,propyl and isopropyl).

"Lower alkoxy" denotes straight or branched chain alkoxy groups of 1 to6 carbon atoms (e.g. methoxy, ethoxy and isopropoxy).

"Lower alkanoyl" signifies moieties derived from alkanecarboxylic acidmoieties having 1 to 6 carbon atoms (e.g. formyl, acetyl, propionyl,etc.).

"Halogen" includes all four halogens, i.e. fluorine, chlorine, bromine,and iodine.

"Lower alkylene" refers to straight and branched chain alkylene groupshaving from 1 to 6 carbon atoms (e.g. methylene, ethylene andpropylene).

"Aryl" designates mononuclear aromatic hydrocarbon groups such asphenyl, tolyl, etc. which can be unsubstituted or substituted in one ormore positions with a lower alkylenedioxy, a halogen, a nitro, a loweralkyl or a lower alkoxy substituent, and polynuclear aryl groups such asnaphthyl, anthryl, phenanthryl, azulyl, etc., which can be unsubstitutedor substituted with one or more of the aforementioned groups. Thepreferred aryl groups are the substituted and unsubstituted mononucleararyl groups, particularly phenyl.

Of the inorganic acid anions there are preferred chlorine, bromine andiodine ions or the hydrosulfate ion and of the organic acid anions thereis preferred the tosyloxy ion.

"Alkali metal" includes all alkali metals such as lithium, sodium,potassium, rubidium and cesium.

In the pictorial representation of the compounds given throughout thisapplication, a ( ) tapered line indicates a substituent which is pointedout of the plane of the paper towards the reader and the (---) brokenline indicates a substituent which is pointed into the plane of thepaper away from the reader.

In accordance with a preferred process of the present invention, acompound of the formula: ##STR6## is oxidized with a cerium(IV) salt orcomplex to form quinones of the formulas: ##STR7## wherein R is loweralkyl, R₁ and R₂ each are lower alkyl or R₁ is phenyl and R₂ ishydrogen; and R₃ is hydrogen or hydroxy.

In carrying out this oxidation, any conventional cerium(IV) salt orcomplex can be utilized. Suitable cerium compounds are, for example,cerium sulfate or cerium ammonium nitrate. The oxidation is convenientlycarried out in an inert organic solvent which is miscible with water(e.g. acetonitrile, tetrahydrofuran and the like) at a temperature ofabout -10° C. to about 40° C. Preferably, the oxidation occurs at atemperature between about 10° C. and about 30° C.

Compounds II, III or mixtures thereof (which mixtures are separable bychromatography, e.g. on silica gel) can be treated with an acid toobtain a compound of the formula: ##STR8## wherein R₃ is as above.Suitable acids include mineral acids (e.g. dilute sulfuric acid, dilutehydrochloric acid, dilute phosphoric acid and the like) as well asorganic acids (e.g. formic acid, acetic acid, trifluoroacetic acid,p-toluenesulfonic acid and the like). The reaction is also convenientlyeffected, especially in the case of the use of a mineral acid, in aninert organic solvent which is miscible with water such as loweralcohols (e.g. methanol, ethanol, propanol, etc.), ether (e.g. dioxan,tetrahydrofuran etc., diethyleneglycol and dimethyl ether),acetonitrile, dimethylformamide and the like, at a temperature of aboutroom temperature to about 100° C. Preferably, the reaction proceeds fromabout room temperature to about 70° C.

Where the previously described oxidation of compound I is carried out inan acid medium, compound I can thereby be converted directly intocompound IV.

Compound IV can then be converted by reductive aromatization into achromane derivative of the formula: ##STR9## with cleavage of thehydroxy group where R₃ is other than hydrogen.

Where R₃ in the compound of formula IV is hydrogen, the reductivearomatization is conveniently effected by hydrogen in the presence of acatalyst (e.g. palladium or platinum) with or without a carrier, as wellas by complex hydrides (e.g. lithium aluminum hydride,diisobutylaluminum hydride, NaAlH₂ (OCH₂ CH₂ OCH₃)₂ and the like) in asuitable organic solvent or also by zinc in acetic acid and the like.

Where R₃ in the compound of formula IV signifies hydroxy, the reductivearomatization is conveniently effected with previous cleavage of thehydroxy group. This cleavage can be carried out by treatment withhydrogen in the presence of a catalyst such as palladium with or withouta carrier material, as well as in the presence of a catalytic amount ofa mineral acid (e.g. perchloric acid, hydrochloric acid and the like)which does not poison the catalyst, or in the presence of a strongorganic acid (e.g. p-toluenesulfonic acid and the like). Anyconventional hydrogenation catalyst can be utilized in carrying out thisreaction.

Alternatively, the conversion of compound IV, wherein R₃ signifies thehydroxy group, into compound V can also be carried out in a "one-potprocess". That is, the reaction can proceed without any isolation of theformed intermediate products of the formulae IIA, III or IV, wherein Rrepresents hydrogen. The compound of the formula: ##STR10## which isobtained after the cleavage of the hydroxy group from the compound offormula IV spontaneously converts in the presence of oxygen into acompound III, wherein R₃ signifies hydrogen. The further conversion ofcompound III into compound V is then effected as previously stated. Ifit is desired to produce the compound of formula IIIa from the compoundof formula IV, the reduction is carried out in an oxygen-freeatmosphere, i.e. under nitrogen.

The compound of the formula V is known and can be converted in a knownmanner into the corresponding (likewise known) aldehyde of the formula:##STR11## wherein R_(x) is lower alkyl, lower alkanoyl or benzyl.Aldehyde VI can then be converted into natural (2R, 4'R,8'R)-α-tocopherol, likewise in a known manner. For example, aldehyde VIcan be reacted with a compound of the formula: ##STR12## via a Wittigreaction and subsequent catalytic hydrogenation.

In accordance with the present invention, it is hereby possible tomanufacture the optically active adehyde VI or compound V which arerequired for the manufacture of natural (2R, 4'R, 8'R)-α-tocopherol in asynthetic manner from optically active starting material with retentionof the absolute configuration at the tertiary carbon atom.

The compounds of the above formula I, used as the starting material inthe inventive process, can be manufactured, depending on thesignificance of the substituents R₃, according to following Scheme I orII.

Compound I, wherein R₃ is hydrogen, can be prepared in accordance withScheme I. ##STR13##

In Scheme I, the substituents R, R₁ and R₂ are as above; R₃ is hydrogen;R₄ is benzyl; R₅ is lower alkyl; X is aryl and Y is an anion of anorganic or inorganic acid.

Compound VII, used as the starting material in Scheme I, is known.

The conversion of compound VII into compound VIII can be effected in aknown manner. For example, compound VII can be reacted with thionylchloride in an inert organic solvent (e.g. dimethylformamide or anether) at a temperature of about 0° C. to about 40° C. followed byreduction of the obtained acid chloride (e.g. with sodium borohydride indimethylformamide).

The conversion of compound VIII into compound IX, i.e. the cleavage ofbenzyl R₄, can likewise be effected in a known manner. Conveniently,this cleavage is carried out by catalytic hydrogenation. Any organicsolvent which is inert under the reaction conditions can be convenientlyutilized. Suitable solvents include ethyl acetate, methanol, ethanol andthe like. A typical catalyst is palladium/carbon catalyst.

The conversion of compound IX into compound X can be carried out in aknown manner. For example, compound IX can be reacted with a2,2-di-lower alkoxypropane (e.g. 2,2-dimethoxypropane) or a di-loweralkyl-ketone (e.g. acetone) or also with benzaldehyde, in the presenceof a catalytic amount of an acid, (e.g. p-toluenesulfonic acid,phosphorus oxychloride, sulfuric acid and the like), at a temperature ofabout 0° C. to about 50° C.

The conversion of compound X into compound XI can be effected directlyand in a known manner. Conveniently, the conversion is effected withdiisobutylaluminium hydride in an inert organic solvent such as an etheror hydrocarbon (e.g. hexane and the like), at a temperature of about-60° C. to about -80° C.

The conversion of compound XII into compound XIII can be carried out ina known manner. For example, the conversion can be effectuated byreacting compound XII with triphenylphosphine in toluene or benzene.

The reaction of compound XI with compound XIII to give a compound offormula I is effected in a known manner. Illustratively, a Wittigprocedure can be utilized. In so doing, the Wittig components arereacted with one another in the presence of a strong base, (e.g. in thepresence of an alkali metal alcoholate, such as sodium methylate, or inthe presence of an optionally alkyl-substituted alkylene oxide,especially in the presence of ethylene oxide or 1,2-butylene oxide)optionally in a solvent, (e.g. in a chlorinated hydrocarbon, such asmethylene chloride, or also in dimethylformamide) in a temperature rangebetween room temperature and the boiling point of the reaction mixture.

Compound I, wherein R₃ is hydroxy, can be manufactured in accordancewith following Scheme II. ##STR14##

In Scheme II, the substituents R, R₁ and R₂ are as above and R₃ ishydroxy.

Compounds XIV and XVI, used as the starting material in the Scheme II,are known or are analogs of known compounds. In the latter situation,the compounds of formulas XIV and XVI can be obtained readily in ananalogous manner to the manufacture of the known compounds. On thecontrary, compound XV is novel and constitutes an object of the presentinvention.

The reaction of compound XIV to yield aldehyde XV can be effected in aknown manner. Conveniently, the reaction is carried out by an oxidationagent chromium trioxide in pyridine or pyridine chlorochromate and thelike) in an inert organic solvent (e.g. chloroform, methylene chloride,pyridine, etc.) and at a temperature of about 0° C. to about 40° C.

The reaction of compound XV with compound XVI is likewise effected in aknown manner. Conveniently, the reaction proceeds in an organic solventwhich is inert under the reaction conditions, such as an ether (e.g.diethyl ether, tetrahydrofuran and the like) and at a temperaturebetween about 0° C. and the reflux temperature of the reaction mixture.

The following non-limiting Examples illustrate the invention. Unlessotherwise indicated, temperature is expressed in degrees Celsius and theether is diethyl ether.

EXAMPLE 1 Manufacture of ethyl(R)-2-benzyloxy-3-hydroxy-2-methyl-propionate

To a solution of 34.2 g of ethyl (R)-2-benzyloxy-2-methyl-monomalonatein 60 ml of methylene chloride were added dropwise while stirring at 5°,11 g of dry dimethylformamide, followed by 11 ml of freshly distilledthionyl chloride. The reaction mixture was thereupon left to stand atroom temperature for 20 hours with exclusion of moisture. The volatilecomponents were removed by distillation at 80°, firstly at 12 mmHg andthen at 0.1 mmHg. The residual liquid was finally distilled at 120° and0.08 mmHg, there being obtained 33.4 g of a colorless oil. To this oilthere was added dropwise at -30° and while stirring for 45 minutes asolution of 3.05 g of sodium borohydride in 50 ml of drydimethylformamide. The resulting mixture was stirred at room temperaturefor a further 3 hours. 5 ml of 1-N sodium bicarbonate solution wereadded dropwise thereto while stirring, followed by 10 g of solid sodiumbicarbonate, whereupon the stirring was continued during a further 1hour. The reaction mixture then was filtered. The residue was washedwith 90% dimethylformamide and the greater part of the solvent wasremoved from the filtrate. The residue was taken up in 250 ml of etherand washed twice with 100 ml of distilled water each time and then with50 ml of saturated brine. After removal of the solvent, impurities weredistilled off at 120°/0.1 mmHg and there were obtained 22 g ofethyl(R)-2-benzyloxy-3-hydroxy-2-methyl-propionate, [α]_(D) =+2.57°(undiluted).

EXAMPLE 2 Manufacture of ethyl (R)-2,3-dihydroxy-2-methyl-propionate

22 g of ethyl (R)-2-benzyloxy-3-hydroxy-2-methyl-propionate(manufactured in accordance with Example 1) in 150 ml of ethyl acetatewere hydrogenated with hydrogen gas in the presence of 11 g of 5% byweight palladium/carbon catalyst up to the cessation of the hydrogenuptake. The catalyst was filtered off, washed with ethyl acetate (2×50ml), the filtrate was concentrated in the vacuum and the residual oilwas distilled at 56°-57°/0.1 mmHg. There were obtained 12.7 g of ethyl(R)-2,3dihydroxy-2-methylpropionate in the form of a colorless viscousliquid. [α]_(D) =+0.339° (undiluted);=11.6° (c=2.12 in chloroform).

EXAMPLE 3 Manufacture of ethyl(R)-2,2,4-trimethyl-1,3-dioxolan-4-carboxylate

500 mg of p-toluenesulfonic acid were added to 10.7 g of ethyl(R)-2,3-dihydroxy-2-methylpropionate, dissolved in 35 ml of dry, freshlydistilled 2,2-dimethoxypropane, and the mixture was stirred at roomtemperature overnight. The excess dimethoxypropane was removed at 45°/12mmHg and the residue was vigorously stirred for 30 minutes with 5 ml of1-N sodium bicarbonate. Then, 150 ml of ether were added thereto and theaqueous phase was separated. The ether solution was washed withsaturated brine and then dried over sodium sulfate. After evaporation ofthe solvent, the product was distilled and there were obtained 11.2 g ofethyl (R)-2,2,4-trimethyl-1,3-dioxolan-4-carboxylate in the form of acolorless liquid; boiling point 81°/15 mmHg.

EXAMPLE 4 Manufacture of (R)-4-formyl-2,2,4-trimethyl-1,3-dioxolan

To a solution of 5 g of ethyl(R)-2,2,4-trimethyl-1,3-dioxolan-4-carboxylate in 30 ml of anhydrousether, cooled down to -78°, were added dropwise while stirring for about30 minutes, 4.55 g of diisobutylaluminium hydride in 25 ml of anhydrousether. The temperature was held at -78° during the entire addition. Thestirring was continued at -70° for a further 5 hours in order tocomplete the reaction. Excess reagent was then decomposed by cautiousaddition of a mixture of 2 ml of methanol and 2 ml of water, the coolingbath was removed and the reaction mixture was slowly brought to roomtemperature. While vogorously stirring under ice-cooling, 5 ml of 1-Msodium bicarbonate were added thereto. The addition of a total of 3 g ofsolid sodium bicarbonate in small portions led to the precipitation ofaluminium hydroxide. After further vigorous stirring at 0° for 30minutes, the precipitate was filtered off and washed three times with 30ml of ether. The combined ether phases were dried over magnesium sulfateand the solvent was distilled off under normal pressure at about 65°bath temperature. The residue was distilled at about 80° bathtemperature and 12 mmHg and there were thus obtained 3.2 g of(R)-4-formyl-2,2,4-trimethyl-1,3-dioxolan.

A once more distilled and worked-up sample was characterized as thesemicarbazone and the sample had a melting point of 201°-203°.

EXAMPLE 5 Manufacture of(S)-4-(2,5-dimethoxy-3,4,6-trimethyl-phenethyl)-2,2,4-trimethyl-1,3-dioxolan

1.84 g of (R)-4-formyl-2,2,4-trimethyl-1,3-dioxolan, 11.0 g of2,5-dimethoxy-3,4,6-trimethylbenzyl-triphenylphosphonium chloride and3.3 g of finely ground anhydrous potassium carbonate were heated atreflux for 30 hours in 25 ml of dry acetonitrile (dried over phosphoruspentoxide and distilled over potassium carbonate) in the presence of 55mg of 18-crown-6 (1,4,7,10,13,16-Hexa-oxo-cyclooctadecane) thesuspension being vigorously stirred. Thereupon, the brown suspension waschromatographed on 400 g of silica gel with toluene-methylacetate-pentane (20:3:3 parts by volume) as the elution agent. Afterbulb-tube distillation at 170° (bath temperature)/0.2 mmHg, there wereobtained 2.57 g of(S)-4-(2,5-dimethoxy-3,4,6-trimethyl-styryl)-2,2,4-trimethyl-1,3-dioxolanas a colorless viscous oil; [α]_(D) ²⁰ =+17.9° (c=2.1 in chloroform).

A solution of 2.51 g of(S)-2-(2,5-dimethoxy-3,5,6-trimethyl-styryl)-2,2,4-trimethyl-1,3-dioxolanin 50 ml of ethyl acetate were shaken together with 0.5 g ofplatinum/carbon catalyst (10% by weight) in a hydrogen atmosphere up tothe cessation of the hydrogen uptake (ca 220 ml; ca 1 hour). Thereupon,the catalyst was filtered off and washed with ethyl acetate. Afterevaporation of the solvent, followed by a bulb-tube distillation of theresidue at 180° (bath temperature)/0.6 mmHg, there were obtained 2.4 gof(S)-4(2,5-dimethoxy-3,4,6-trimethyl-phenethyl)-2,2,4-trimethyl-1,3-dioxolanas a colorless strongly viscous oil. [α]_(D) ²² =+4.5° (c=2.2 inchloroform).

The 2,5-dimethoxy-3,4,6-trimethylbenzyl-triphenylphosphonium chlorideused as the starting material was manufactured as follows:

25.7 g of 2,5-dimethoxy-3,4,6-trimethylbenzyl chloride in 100 ml oftoluene were heated at reflux with 30 g of triphenylphosphine for 16hours while stirring. A white suspension formed. The precipitate wasfiltered off, washed three times with 50 ml of toluene each time anddried up to constant weight in a high vacuum. There were obtained 53.1 gof the desired product as a white powder with a melting point of230°-231° C.

EXAMPLE 6 Manufacture of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolan-4-ethyl)-p-benzoquinoneand of(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinone

While stirring for 2 minutes at room temperature, 2.01 g of ceriumammonium nitrate in 7.5 ml of water were added dropwise to a solution of550 mg of(S)-4-(3,5-dimethoxy-3,4,6-trimethyl-phenylethyl)-2,2,4-trimethyl-1,3-dioxolanin 7.5 ml of acetonitrile. After 2 minutes of additional stirring, thereaction mixture was extracted three times with 20 ml of chloroform eachtime. The combined organic extracts were dried over sodium sulfate,whereafter the solvent was removed. After chromatography of the obtainedresidue on silica gel with benzene/ethyl acetate (2:1 parts by volume)and ethyl acetate, there were obtained 266 mg of(S)-(+)-2,3,6-trimethyl-5-(2,2,4-trimethyl-1,3-dioxolan-4-ethyl)-p-benzoquinoneand 177 mg of(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinonein the form of yellow needles with a melting point of 111°-112°.

EXAMPLE 7 Manufactured of(3R,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-1-benzoxepin-7-one

A mixture of the quinones obtained in accordance with Example 6 was leftto stand at room temperature for 16 hours in a mixture of 12.7 ml ofmethanol and 3.8 ml of 1-N aqueous hydrochloric acid. Thereupon, theacid was neutralized by addition of solid sodium bicarbonate. Thereaction mixture was poured into 50 ml of saturated brine and theproduct was extracted three times with 50 ml of ether. The combinedether extracts were dried over sodium sulfate and then evaporated. Bychromatography of the residue on 40 g of silica gel with toluene/ethylacetate (9:1 and 2:1 parts by volume) as the elution agent thereresulted 315 mg of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-1-benzoxepin-7-one.After recrystallization from hexane, the product had a melting point of99°-100°.

In an analogous manner, from the individual quinones manufactured inaccordance with Example 6 there could likewise be manufactured(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-1-benzoxepin-7-one.

EXAMPLE 8 Manufacture of(S)-(+)-6-hydroxy-2,5,7,8-tetramethyl-chroman-2-methanol

250 mg of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-1-benzoxepin-7-onein 50 ml of ethanol were hydrogenated with hydrogen gas during 10minutes in the presence of 200 mg of 5% by weight palladium/carbon.Thereupon, the catalyst was filtered off, the solvent was evaporated offand the residue was chromatographed on silica gel with benzene/ethylacetate (2:1 parts by volume). There was obtained pure(S)-(+)-6-hydroxy-2,5,7,8-tetramethyl-chroman-2-methanol as colorlesscrystals with a melting point of 127°-128°.

EXAMPLE 9 Manufacture of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-1-benzoxepin-7-one

160 mg of(S)-4-(2,5-dimethoxy-3,4,6-trimethylphenethyl)-2,2,4-trimethyl-1,3-dioxolanin 20 ml of methanol and 4 ml of 0.8-N sulfuric acid were stirred atroom temperature overnight with a suspension of 400 mg of ceriumsulfate. Thereupon, sodium bicarbonate was added thereto and thereaction mixture was extracted with methylene chloride. After drying ofthe combined extracts over magnesium sulfate and removal of the solvent,there were obtained 134 mg of a viscous yellow oil. By chromatography ofthis oil on silica gel with benzene/ethyl acetate (2:1 parts by volume),there were obtained 17 mg of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-1-benzoxepin-7-one,which had a melting point of 99°-100° after recrystallization fromhexane.

EXAMPLE 10 Manufacture of(S)-2,2,4-trimethyl-1,3-dioxolan-4-acetaldehyde

4.33 g of (S)-2,2,4-trimethyl-1,3-dioxolan-4-ethanol dissolved in 7 mlof absolute methylene chloride were added dropwise to a suspension of7.59 g of pyridine chlorochromate in 30 ml of absolute methylenechloride. The reaction mixture was stirred at room temperature for 3hours. By addition of 75 ml of ether, the chromium salt was precipitatedand separated by filtration over 120 g of Kieselgel. After removal ofthe solvent on a rotary evaporator and distillation of the residue at90°-100°/10 mmHg, there were obtained 3.00 g of(S)-2,2,4-trimethyl-1,3-dioxolan-4-acetaldehyde. [α]_(D) ²⁰ =-35.5°(c=1.50; n-hexane).

EXAMPLE 11 Manufacture ofα-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2,4-(S)-trimethyl-1,3-dioxolan-4-ethanol

To 0.8 g of magnesium shavings activated with methyl iodide was addeddropwise a solution of 7.77 g of1-bromo-2,5-dimethoxy-3,4,6-trimethylbenzene in 20 ml of absolutetetrahydrofuran at a rate such that the solvent was brought just toboiling. Subsequently, the reaction mixture was boiled under reflux foran additional hour. To this Grignard solution, cooled down to 0°, wereadded dropwise 5.0 g of (S)-2,2,4-trimethyl-1,3-dioxolan-4-acetaldehyde.Subsequently, the reaction mixture was stirred at room temperature for afurther 4 hours and under reflux for 15 minutes. For the working-up, thereaction mixture was cooled down to 0°, it was treated with 10 ml ofsaturated ammonium chloride solution followed by 10 ml of 2-N sulfuricacid and extracted with a total of 0.5 l of ether. The organic phase waswashed neutral with water and dried over magnesium sulfate. Afterremoval of the solvent on a rotary evaporator and drying of the residuein a high vacuum, there were obtained 10.5 g of a highly viscous oil,which, for purification, was chromatographed on 450 g of Kieselgel withether/hexane/acetic ester (4:4:1 parts by volume). The yield ofα-(2,5-dimethoxy-3,4,6-trimethylphenyl)-2,2,4-(S)-trimethyl-1,3-dioxolan-4-ethanolamounted to 8.83 g; [α]_(D) ²⁰ =-5.5° (c=1.20; CHCl₃).

EXAMPLE 12 Manufacture of2,3,6-trimethyl-5-(2,2,4-(S)-trimethyl-1,3-dioxolan-4-β-hydroxyethyl)-p-benzoquinone.

A solution of 3.38 g ofα-(2,5-dimethoxy-3,4,6-trimethyl-phenyl)-2,2,4-(S)-trimethyl-1,3-dioxolan-4-ethanolin 40 ml of acetonitrile was poured into a solution of 11.2 g of Ce(NH₄)₂ (NO₃)₆ in 40 ml of water and stirred at room temperature for 3.5minutes. Subsequently, the yellow solution was extracted with a total of0.5 l of methylene chloride. The combined organic phases were washedneutral firstly with saturated sodium bicarbonate solution, then withsaturated common salt solution and dried over magnesium sulfate. Afterremoval of the solvent on the rotary evaporator at 50°, there wereobtained 3.30 g of2,3,6-trimethyl-5-(2,2,4-(S)-trimethyl-1,3-dioxolan-4-β-hydroxyethyl)-p-benzoquinone,which was uniform in a thin-layer chromatogram. The product could beseparated by chromatography on Kieselgel with toluene/pentane/aceticacid methyl ether (20:3:3 parts by volume) into the two epimers, whichshowed the following rotation values: [α]_(D) ²⁰ =-60.2° (c=1.6; CHCl₃)and [α] _(D) ²⁰ =+17.3° (c=2.0; CHCl₃).

EXAMPLE 13 Manufacture of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one

A mixture of 2.33 g of2,3,6-trimethyl-5-(2,2,4-(S)-trimethyl-1,3-dioxolan-4-β-hydroxyethyl)-p-benzoquinone,80 ml of dioxan and 16 ml of 2-N sulfuric acid was stirred at 70° for 2hours. The cooled solution was neutralized by addition of solid sodiumhydrogen carbonate and was subsequently extracted with methylenechloride. The combined organic phases were washed firstly with asaturated common salt solution, then dried with magnesium sulfate. Afterremoval of the solvent on a rotary evaporator at 50°, there wereobtained 2.16 g of the(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-onewhich was uniform in the thin-layer chromatogram.

For the determination of the optical rotation, a portion of the productwas chromatographed on Kieselgel with toluene/acetic ester (1/1 parts byvolume): [α]_(D) ²⁰ =+178° (c=3.8 CHCl₃).

EXAMPLE 14 Manufacture of(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol

A mixture of 0.59 g of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one,0.7 g of palladium-on-barium sulfate (5% by weight) and 3 drops ofconcentrated perchloric acid in 20 ml of methanol was hydrogenated withca 120 ml of hydrogen under normal pressure. Subsequently, 2 ml of 2-Nsulfuric acid were added and air was conducted into the mixture for 15hours. The reaction mixture was again hydrogenated with ca 25 ml ofhydrogen. After removal of the catalyst by filtration over Hyflo, thefiltrate was treated with dilute sodium bicarbonate solution andextracted with ether. The combined organic phases were dried overmagnesium sulfate. After distillation of the solvent on a rotaryevaporator, there were obtained 0.62 g of brown crystals, which, forpurification, was chromatographed on Kieselgel with acetic ester/toluene(1/1 parts by volume). The resulting(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol crystallizedfrom methylene chloride/hexane at a yield of 487 mg; melting point126.5°- 128.5°.

EXAMPLE 15 Manufacture of(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol

108 mg of(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-onewere hydrogenated at normal pressure together with 100 mg of palladiumon carbon (5% by weight) and 20 mg of p-toluenesulfonic acid in 20 ml ofmethanol. The uptake of hydrogen amounted to 22 ml and the reactionduration amounted to 1 hour. After filtration of the catalyst andremoval of the solvent on a rotary evaporator, the residue waschromatographed on a precoated PLC (preparative layer chromatography)Kieselgel plate (Merck) with toluene/acetic ester (1/1 parts by volume),whereby the oxidation to the(S)-(+)-5-(3,4-dihydroxy-3-methyl-1-butyl)-2,3,6-trimethyl-p-benzoquinonetook place. There were obtained 70 mg of this product with a meltingpoint of 112°-113°.

The further conversion of this compound into the(3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-3,6,8,9-tetramethyl-3,9a-1-benzoxepin-7-oneas well as its conversion into the(S)-(+)-6-hydroxy-2,5,7,8-tetramethylchroman-2-methanol was effected ina manner analogous to that of Examples 7 or 8.

We claim:
 1. A compound of the formula: ##STR15##